The present invention relates to novel polymorphic forms of risperidone. The present invention also relates to methods of making polymorphic forms of risperidone.
RISPERDAL(copyright) (risperidone) is an antipsychotic agent belonging to a new chemical class, the benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H -pyrido[1,2-a]pyrimidin-4-one.
U.S. Pat. No. 4,804,663, the contents of which are incorporated by reference, describes a synthesis of risperidone. Risperidone may be prepared by condensation of the following two intermediates, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I) and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound II) in dimethylformamide (DMF) in basic conditions (Na2CO3 or K2CO3) with catalytic amount of potassium iodide (KI). The crude risperidone product (III) is crystallized from a mixture of DMF and isopropanol with an overall yield of 46%. 
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
An object of the processes of the present invention is to provide more efficient and quicker methods for making pure risperidone. We have now found that the synthesis of risperidone from compounds I and II can done in acetonitrile and isopropanol, without using DMF, to give an improved and higher yield of about 75%.
The present invention provides a process for the preparation of risperidone from the following two intermediates, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I) and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound II) in acetonitrile.
It has also been found that the crude risperidone can be efficiently crystallized in high yield from an alcohol, for example, isopropanol, butanol, ethanol, or methanol; or from a ketone, for example, acetone or ethyl methyl ketone, without the need of using DMF, which is harmful to humans and is a very difficult solvent to remove.
Polymorphs of risperidone are mentioned in the Summary Basis of Approval (SBA) of New Drug Application 20-272 and 20-588, however the SBA does not identify them by recognized methods of crystal structure identification such as x-ray diffraction.
The present invention also provides forms of risperidone designated risperidone Form A, Form B and Form E.
The present invention further provides a process for making risperidone comprising reacting Compound I with Compound II to form crude risperidone (III) in a solvent selected from the group consisting of acetonitrile, isopropanol, methyl ethyl ketone and iso-butanol.
In another embodiment, the crude risperidone is recrystallized from an alcohol; a mixture of alcohols; a mixture of water and alcohol; or from a ketone, e.g., acetone. In another embodiment, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, propanol, butanol, sec-butanol, iso-butanol and t-butanol. In another embodiment, the alcohol is isopropanol. In another embodiment, the alcohol is acetonitrile. In another embodiment, the alcohol is isopropanol. In another embodiment, the alcohol is iso-butanol. In another embodiment, the ketone is acetone. In another embodiment, the acetone is methyl ethyl ketone.
The present invention also provides risperidone Form A which is characterized by x-ray powder diffraction peaks at 14.2xc2x10.2, 21.3xc2x10.2 degrees two-theta. The present invention also provides risperidone Form A of further characterized by x-ray powder diffraction peaks at 10.6xc2x10.2, 11.4xc2x10.2, 16.4xc2x10.2, 18.9xc2x10.2, 19.9xc2x10.2, 22.5xc2x10.2, 23.3xc2x10.2, 25.4xc2x10.2, 27.6xc2x10.2, 29.0xc2x10.2 degrees two-theta.
The present invention also provides a risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in FIG. 1.
The present invention also provides risperidone Form B which is characterized by x-ray powder diffraction peaks at 14.0xc2x10.2 and 21.7xc2x10.2 degrees two-theta.
The present invention also provides a risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in FIG. 2.
The present invention also provides risperidone Form B which is further characterized by x-ray powder diffraction peaks at 10.8xc2x10.2, 11.9xc2x10.2, 12.6xc2x10.2, 14.0xc2x10.2, 17.5xc2x10.2, 18.3xc2x10.2, 19.9xc2x10.2, 21.0xc2x10.2, 21.7xc2x10.2 degrees two-theta.
The present invention also provides risperidone Form E which is characterized by x-ray powder diffraction peaks at 16.5xc2x10.2, 21.7xc2x10.2 degrees two-theta.
The present invention also provides risperidone Form E which is further characterized by x-ray powder diffraction peaks at 16.5xc2x10.2, 12.6xc2x10.2, 21.7xc2x10.2, 15.6xc2x10.2, 17.0xc2x10.2, 18.4xc2x10.2, 19.1xc2x10.2, 21.3xc2x10.2, 24.0xc2x10.2, 24.9xc2x10.2, 27.0xc2x10.2 degrees two-theta.
The present invention also provides a risperidone polymorph that is characterized by a powder x-ray diffraction pattern substantially as depicted in FIG. 3.
The present invention also provides a process for preparing risperidone Form B comprising the steps of: dissolving risperidone in a substantially water soluble alcohol having 1 to 4 carbon atoms where the ratio of risperidone to alcohol is about 1:7.5 to about 1:9; adding water to facilitate precipitation; and isolating risperidone Form B.
The present invention also provides a process for preparing risperidone Form B comprising the steps of: dissolving risperidone in chloroform; adding cyclohexane or hexane to facilitate precipitation; and isolating risperidone Form B.
The present invention also provides a process for preparing risperidone Form B comprising the steps of: dissolving risperidone in an aqueous solution of HCl; adding an aqueous solution of Na2CO3; and isolating risperidone Form B.
The present invention also provides a process for preparing risperidone Form A comprising the steps of: dissolving risperidone in an organic solvent selected from the group consisting of dimethylformamide, tetrahydrofuran, acetone, benzene, ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethyl sulfoxide, iso-butanol, and ethyl acetate or mixtures thereof; heating the solvent to reflux; cooling the solvent to facilitate precipitation; and isolating risperidone Form A.
The present invention also provides a process for preparing risperidone Form A comprising the steps of: dissolving risperidone in dichloromethane; adding cyclohexane or hexane to facilitate precipitation; and isolating risperidone Form A.
The present invention also provides a method for preparing risperidone Form A comprising the step of: heating risperidone Form B at a temperature of about 25xc2x0 C. to about 80xc2x0 C. for a time sufficient to induce to formation of risperidone Form A; and isolating risperidone Form A. In another embodiment, the heating takes place under reduced pressure or at atmospheric pressure. In another embodiment, the temperature is about 80xc2x0 C. In another embodiment, the time for heating is about 16 to about 20 hours.
The present invention also provides a process for preparing risperidone Form E comprising the steps of: dissolving risperidone in isopropanol where the ratio of risperidone to isopropanol is about 1:12; adding water to facilitate precipitation; and isolating risperidone Form E.